Are some people wired to fall for placebos?

Some people are born believers. Fake surgeries have been shown to relieve traumatic knee pain; “dummy pills” have wiped away migraines. A new report from Harvard University describes how certain genes predispose people toward believing placebos, or experiencing the “placebo effect.”

It also tackles corresponding ethical questions. For example, could knowing who’s prone to placebos one day determine who is first in line to receive cutting-edge medicine? The report was published on Monday in the journal, Trends in Molecular Medicine.

The placebo effect extends beyond how a patient’s body reacts to a sugar pill or an otherwise inert treatment. The phenomenon starts the moment a patient walks into a doctor’s office.

“Everything from your physician’s mood to their office décor to whether or not they wear a stethoscope can have a profound influence on how some patients respond to treatment,” says co-author Kathryn Hall, a senior fellow at the Program in Placebo Studies at Harvard Medical School’s Beth Israel Deaconess Medical Center in Boston. Though a placebo won’t stop cancer or a virus, being duped benefits a wide spectrum of disorders.

The million-dollar question is knowing who will exhibit the placebo effect. Over the last four years, Hall and other scientists have turned to genetic screening for clarity. They have found genetic traits – dubbed “the placebome” – that make certain people more prone to the placebo effect, according to the report.

But genetic screening for placebo response raises ethical questions. If the placebo response is innate, then it likely varies by gender, age, ethnicity and other demographics. In clinical trials, placebo takers represent a blank canvas against which researchers can compare people receiving actual treatment. Is it ethical then to deny access to an experimental, potentially life-altering drug if a person’s placebo predisposition could cloud the results?

Take, for example, irritable bowel syndrome. Nearly 40 percent of IBS patients elicit a reaction to taking placebos. In 2012, Hall and her colleagues examined a trait that may explain why. They looked at a brain enzyme, catechol-Omethyltransferase (COMT), which influences the human perception of pain. COMT does so by controlling the production of dopamine within parts of the frontal lobes that govern motivation and our experience of rewards. The gene for COMT comes in two different forms – “met” and “val”, based on mutations in its DNA sequence. People who inherit two copies of the “met” gene from their parents live with extra dopamine in their rewards circuits and, as a consequence, are more sensitive to pain. Those with “val” harbor less dopamine and are more resilient to pain.

In Hall’s study, patients with irritable bowel syndrome received a placebo — fake acupuncture where the needles were pressed but didn’t pierce the skin – or they sat for three weeks on a “waitlist” without treatment. Patients with “met” had a bigger reduction in pain symptoms, scoring an average of 50 points lower on a 500-point scale of discomfort when compared to those with “val.” The contrast between the genetic groups was twice as dramatic if doctors augmented the placebo effect by being extra nice to their patients.

Still unknown is whether these placebo genes generalize to other conditions. “[Some] people with irritable bowels have a [placebo] susceptibility in the frontal lobes that may not happen for someone with chronic lower back pain,” says Jon-Kar Zubieta, a psychiatrist and radiologist at the University of Michigan.

Some people’s brains react differently to natural painkillers – endorphins – levels of which have been implicated as a source of chronic pain.

Zubieta’s team showed last October that a single mutation in a protein responsible for recognizing endorphins can intensify pain relief after receiving a placebo. In this case, the placebo effect was mediated by activity in a different brain network relative to the one for irritable bowel syndrome. And in 2008, a team from Sweden uncovered how a gene involved with serotonin production could predict if a sugar pill would help a patient with social anxiety disorder.

In these cases, the placebo effect hijacked natural pathways that are typically affected by real drugs. That’s a conundrum, says Zubieta, because if you have a disease where the power of suggestion hits the same nerves as your experimental drug, then how can you tell if the new meds are working?

It remains a mystery how drug companies will respond to the discovery of placebo genes. For instance, should white Americans be excluded from clinical trials for irritable bowel syndrome, given they are four times as likely to be a “met” and experience a placebo effect relative to black Americans? A young biotech company Biometheus is already working on a genetic test to capitalize on COMT variants and streamline clinical trials for drug companies.

“Excluding people from trials is a concern, but I’m skeptical if it will happen in the near future,” says Frank Miller, a retired bioethicist with the National Institutes of Health. Most of the placebo-related mutations identified so far are common, so screening would remove larges swaths of potential patients, he said. Plus, the U.S. Food and Drug Administration could restrict who can ultimately purchase the remedy if it’s only tested on a subset of people, Hall says.

“If the problem is that drugs don’t beat placebo, then we need better drugs,” says Miller.

Still, drug design is increasingly moving toward personalized medicine where people keep tabs on their genetics. (Just ask Angelina Jolie.) Placebome screening could ensure that whether a new medication works well for a niche population, allowing a drug manufacturer to corner the profits.

For instance, placebo responders may need a lower dose of real drugs to experience the same benefit. A lower dosage reduces the chance of side effects, meaning better knowledge of the placebo effect may fine tune and improve treatment for many individuals, Hall says.

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